High-density lipoprotein cholesterol (HDL-C) has a positive effect on endothelial cell and vascular wall function. To our knowledge, there are no studies investigating the use of increasing HDL-C as a neurorestorative therapy to promote brain plasticity and recovery of neurological function after stroke. Based on robust preliminary data that agents which increase HDL-C when administered starting one day after stroke, promote vascular remodeling and significantly reduce functional deficits after ischemic stroke, we seek to develop a novel neurorestorative treatment of ischemic stroke. The following specific aims and associated hypotheses are designed to develop this restorative therapy and to investigate their molecular mechanisms in a pre-clinical rodent model of middle cerebral artery occlusion (MCAo). Aim 1 will investigate safety, toxicity and neurorestorative effects of select agents which increase HDL-C after stroke in adult mice. We hypothesize that treatment of stroke in mice with agents that increase HDL-C {Niaspan (N) and TO901317 (T)} initiated at one day after stroke onset improves neurological functional recovery, and is safe and well tolerated. The minimally toxic and more effective agent (Niaspan or TO901317, N-or-T) that promotes functional outcome after stroke will be identified and will be employed in the following Aims 2 & 3. Aim 2 will elucidate the effect of N-or-T treatment of stroke on the regulation of angiogenic factors and vascular remodeling, i.e. cerebral blood flow (CBF), angiogenesis, and arteriogenesis. The contribution of vascular remodeling induced by N-or-T in functional outcome after stroke will be tested. We hypothesize that N-or-T treatment of stroke induces endothelial nitric oxide synthase (eNOS) and Angiopoietin-1(Ang1)/Tie2 signaling activity, which increase CBF, angiogenesis and arteriogenesis after stroke in mice. Inhibition of vascular remodeling by an anti-angiogenic factor, Angiostatin (K1-5), impairs functional outcome after stroke and attenuates the N-or-T induced restorative effect after stroke in mice. Aim 3 will identify the molecular signaling pathways by which N- or-T induces vascular remodeling and functional recovery after stroke. The contribution of eNOS and Ang1/Tie2 to N-or-T induced restorative effect and vascular remodeling will be examined by using eNOS knockout mice and a specific antibody to Tie2 in mice subjected to stroke and treated with N-or- T, respectively. The underlying hypotheses are that: Increasing HDL-C agent (N-or-T) fosters functional recovery after stroke by increasing the expression and activation of eNOS and Ang1/Tie2 signaling in cerebral tissue; these factors promote vascular remodeling via the induction of angiogenesis and arteriogenesis, which augment functional recovery. This study provides a new and highly effective way to treat stroke and may permit translation of our findings of the restorative therapeutic benefit of agents which increase HDL-C in experimental stroke to the patient. PUBLIC HEALTH RELEVANCE: Stroke is the third leading cause of morbidity and long-term disability. High-density lipoprotein cholesterol (HDL-C) has a positive effect on endothelial cell and vascular wall function. Based on robust preliminary data that agents which increase HDL-C when administered starting one day after stroke, promote vascular remodeling and significantly reduce functional deficits after ischemic stroke, we seek to develop a novel neurorestorative treatment of ischemic stroke. Niaspan and TO901317 are effective medications for increasing HDL-C. Thus, we propose to develop neurorestorative therapy for stroke using agents that increase HDL-C and to investigate their molecular mechanisms in a pre-clinical rodent model of middle cerebral artery occlusion (MCAo). This study provides a new and highly effective way to treat stroke and may permit translation of our findings to the patient.